KR20170037154A - Preparation method of chromanone 2-carboxylic acid or chroman 2-carboxylic acid derivatives - Google Patents
Preparation method of chromanone 2-carboxylic acid or chroman 2-carboxylic acid derivatives Download PDFInfo
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The present invention relates to chromanone 2-carboxylic acid derivatives, chroman 2-carboxylic acid derivatives, and a process for preparing them, which can be used as intermediates for medicinally active ingredients currently available on the market. Can be usefully used in the production of active ingredients of medicines ("Fidarestat", "repinotan", "nebivolol", etc.) currently used in clinical practice, and in particular, the production of chromanone or chroman 2-carboxylic acid derivatives The method is not only simple in its production process, but also has the effect of producing the target compound in an optically pure form without using a chiral catalyst.
Description
The present invention relates to a chromanone 2-carboxylic acid derivative, chroman 2-carboxylic acid derivative and a method for producing the same, which can be used as intermediates for medicinally active ingredients currently available on the market. , There is an advantage that an optically pure intermediate can be obtained without using a chiral catalyst.
The present invention relates to a process for producing chlmanone 2-carboxylic acid derivatives and chroman-2-carboxylic acid derivatives represented by the following formula (A), which can be widely used as raw materials important for the synthesis of pharmaceuticals, in a racemic or optically pure form ≪ / RTI >
(A)
In the above formula (A)
R 1 and R 2 independently represent hydrogen, halogen, C 1-10 linear or branched alkyl, or C 1-10 straight or branched alkoxy,
R 3 represents hydrogen, straight or branched alkyl of C 1-10 , or benzyl,
X represents hydrogen or oxygen,
The compound represented by the above formula (A) can be prepared in a racemic or optically pure state as a compound having a chiral center at the C-2 position. Both racemic or optically pure forms of chromanone 2-carboxylic acid and chroman 2-carboxylic acid derivatives are known as important raw materials in the synthesis reaction of various medicines. 6-fluoro-chromanone-4-oxo-2-carboxylic acid, a derivative of chromanone 2-carboxylic acid, has been used as a raw material of "Fidarestat" which is effective in relieving symptoms of diabetic neuropathy and retinopathy [ Chem. Pharm. Bull. 1994, 42 , 1474.] Chromanone 2-carboxylic acid is a potent antagonist of the 5-HT 1A receptor and has been used as a raw material, such as "repinotan", which is effective in relieving brain damage caused by stroke [ J. Med. Chem. 2011, 54 , 7986]. "Nebivolol" which is currently in clinical use as a therapeutic agent for hypertension was also prepared from 6-fluoro-chroman-2-carboxylic acid, a chroman 2-carboxylic acid derivative.
In addition, chroman 2-carboxylic acid derivatives have been used as a key material for the production of various compounds exhibiting anticancer, antibacterial, anti-inflammatory and antioxidative activities. [Antitumor activity: Chem. Biol. Drug Des. 2011, 78 , 62; Antibacterial activity: Eur. J. Med. Chem. 2006, 41 , 599 .; Anti-inflammatory action: Arch. Pharm. Res. 2008, 31 , 133 .; Antioxidant activity: Bioorg. Med. Chem. Lett. 2005, 15 , 2745.]
In particular, "fidarestat" and "repinotan" are chiral compounds whose stereocenters are fixed in the compound structure and which are optically pure chromanone-carboxylic acids or racemic chroman- . In addition, even in the case of a compound having the same skeleton having chroman-2-carboxylic acid and a chroman-2-carboxylic acid in a racemic form, the drug efficacy differs greatly depending on the stereostructure, so that an optically pure form of chromanone- The synthesis of carboxylic acid and chroman-2-carboxylic acid in racemic form is very important in terms of pharmaceutical chemistry and organic synthesis.
An example of a drug having an optically pure form of chromanone 2-carboxylic acid or chroman 2-carboxylic acid as a core skeleton structure is shown below.
Generally, racemic chromanone-carboxylic acid derivatives are prepared by condensing 2-hydroxyacetophenone with diethyl oxalate to synthesize chromone-carboxylic acid ethyl ester (ethyl ester chromone 2-carboxylate) Which is obtained by a reduction reaction under a Pd / C catalyst [ Arch. Pharm. Res. 2008, 31 , 133.]. The racemic chroman-2-carboxylic acid derivatives thus prepared are optically isolated using enzymes or [ J. Med. Chem. 2011, 54 , 7986.], optically pure forms of chroman-carboxylic acid derivatives are obtained through selective crystallization after reaction with a chiral amine adjuvant [ Tetrahedron Lett. 2003, 44 . 8563], these methods have the disadvantage that not only the maximum yield does not exceed 50% but also the enantiomer must be discarded.
Synthesis of optically pure forms of chromanone 2-carboxylic acid derivatives via asymmetric synthesis using D-mannitol as a starting material has also been reported, but due to the fact that the intermediate is obtained as a mixture of two diasteromers [Synthetic Communications 2007 , 37 , 3773], an optically pure form of 6-fluoro-chroman-2-carboxylic acid was obtained in low yield. Asymmetric synthesis method [ Tetrahedron 2000, 56 , 6339] using a chiral catalyst [ Angew. Chem. Int. Ed. 2013, 52 , 2555] and chroman-2-carboxylic acid derivatives in an optically pure enantiomerically pure manner have also been reported, but these methods have problems such as a long reaction path, a complicated process for producing a chiral catalyst having a complex structure There are disadvantages.
Accordingly, the present inventors intend to provide a production process capable of effectively synthesizing chromanone 2-carboxylic acid and chroman-2-carboxylic acid derivatives which can be widely used as raw materials important for synthesis of pharmaceuticals, and further, -Carboxylic acid and chroman-2-carboxylic acid derivatives plays a very important role in the pharmaceutical activity, so that chromanone-2-carboxylic acid and chroman-2-carboxylic acid derivatives are optically pure forms To provide a process for effectively producing the same.
It is an object of the present invention to provide chromanone 2-carboxylic acid derivatives and chroman 2-carboxylic acid derivatives that can be used as intermediates of medicinally active ingredients currently on the market.
Another object of the present invention is to provide a process for producing the chromanone 2-carboxylic acid derivative.
It is still another object of the present invention to provide a process for producing the chroman 2-carboxylic acid derivative.
In order to achieve the above object,
The present invention provides an intermediate represented by the following formula (A).
(A)
In the above formula (A)
R 1 and R 2 independently represent hydrogen, halogen, C 1-10 straight or branched chain alkyl, or C 1-10 straight or branched alkoxy;
R 3 represents hydrogen, straight or branched alkyl of C 1-10 , or benzyl;
X represents hydrogen, or oxygen;
The present invention also relates to a process for producing a compound represented by the formula (1)
Acetyl chloride is added to L-malic acid to form 2-acetylsuccinic anhydride, followed by alcoholysis by adding R 3 -OH to thionyl chloride to obtain compound 3a (step 1);
Step (step 2) of obtaining compound 4 through Fridel-Crafts acylation using compound 3b and aluminum chloride;
Dissolving the compound 4 in an organic solvent, adding AlCl 3 and stirring to obtain the dimethylated compound 5 (step 3);
Triphenylphosphine and diethylazodicarboxylate in an organic solvent to obtain a compound 1 by adding the compound 5 obtained in the above step 3 and cyclizing the resulting mixture under mitsunobu reaction conditions 4); and a method for producing the chromanone-2-carboxylic acid derivative represented by the formula (1).
[Reaction Scheme 1]
In the above Reaction Scheme 1,
R 1 to R 3 and
The chromanone 2-carboxylic acid derivative represented by the formula (1) is included in the intermediate represented by the above formula (A).
Further, the present invention provides a compound represented by the following formula (2)
The chromanone 2-carboxylic acid derivative represented by the general formula (1) is introduced into an organic solvent and hydrogen is then introduced in the presence of triethylsilane or palladium / charcoal to obtain a chromanone 2- Carboxylic acid derivative represented by formula (2), which comprises a step of reducing the carbonyl group at the 4-position of the carboxylic acid derivative to produce a chroman-2-carboxylic acid derivative represented by the formula (2) do.
[Reaction Scheme 2]
In the above Reaction Scheme 2,
R 1 to R 3 and
The chroman 2-carboxylic acid derivative represented by the formula (2) is included in the intermediate represented by the above formula (A).
The intermediate represented by the formula (A) according to the present invention can be usefully used for the production of effective components of medicines ("Fidarestat", "repinotan", "nebivolol" The production method of the chroman-2-carboxylic acid derivative is not only simple in its production process but also has the effect of producing the target compound in an optically pure form without using a chiral catalyst.
Hereinafter, the present invention will be described in detail.
The present invention provides an intermediate represented by the following formula (A).
(A)
In the above formula (A)
R 1 and R 2 independently represent hydrogen, halogen, C 1-10 straight or branched chain alkyl, or C 1-10 straight or branched alkoxy;
R 3 represents hydrogen, straight or branched alkyl of C 1-10 , or benzyl;
X represents hydrogen, or oxygen;
The intermediate represented by formula (A) according to the present invention can be used for the preparation of "Fidarestat" (formula B), "repinotan" (formula C), "nebivolol" (formula D) have.
[Chemical Formula B]
≪ RTI ID = 0.0 &
[Chemical Formula D]
Method 1: Chromanone 2- Carboxylic acid Method for producing derivatives
Production method 1 according to the present invention is a simple production process having technological characteristics using optically pure D-malic acid or L-malic acid as a starting material and can be carried out without using a chiral catalyst, There is an effect that a carboxylic acid derivative can be produced in an optically pure form.
As shown in the following Reaction Scheme 1,
Acetyl chloride is added to L-malic acid to form 2-acetylsuccinic anhydride, followed by alcoholysis by adding R 3 -OH to thionyl chloride to obtain compound 3a (step 1);
Step (step 2) of obtaining compound 4 through Fridel-Crafts acylation using compound 3b and aluminum chloride;
Dissolving the compound 4 in an organic solvent, adding AlCl 3 and stirring to obtain the dimethylated compound 5 (step 3);
Triphenylphosphine and diethylazodicarboxylate in an organic solvent to obtain a compound 1 by adding the compound 5 obtained in the above step 3 and cyclizing the resulting mixture under mitsunobu reaction conditions 4); and a method for producing the chromanone-2-carboxylic acid derivative represented by the formula (1).
[Reaction Scheme 1]
In the above Reaction Scheme 1,
R 1 to R 3 and
The chromanone 2-carboxylic acid derivative represented by the formula (1) is included in the intermediate represented by the above formula (A).
In the above Reaction Scheme 1, the substituent R 3 of the compound 3a may be directly substituted with a substituent to be obtained in the objective compound, or a compound in which the substituent R 3 of the compound 3a is a methyl group is used to obtain the desired compound, And the step of replacing the methyl group corresponding to the 3- substituent group with another substituent group.
In Step 1 of Production Method 1 according to the present invention, step 1 is carried out by adding acetyl chloride to L-malic acid to form 2-acetylsuccinic anhydride, followed by alcoholysis by adding R 3 -OH to thionyl chloride, .
In Process 1 of the present invention, Step 2 is a step of obtaining Compound 4 through Fridel-Crafts acylation using Compound 3b and aluminum chloride.
Step 3 is a step of dissolving Compound 4 in an organic solvent, adding AlCl 3 , and stirring to obtain dimethylated Compound 5 in Production Method 1 according to Production Method 1 according to the present invention.
The organic solvent may be selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile (ACN), methanol, t-butanol, diethyl ether, diphenyl ether, diisopropyl ether DIPE), dimethylformamide (DMF), dimethyl acetamide (DMA), chlorobenzene, benzene, toluene, carbon tetrachloride (CCl 4), acetone, trichloroacetic acid, trifluoroacetic acid, hydrochloric acid, chloroform (CHCl 3), etc. Can be used alone or in combination, and dichloromethane (DCM) can be preferably used.
The reaction temperature in step 3 may be 0-30 ° C, preferably 0-10 ° C, and the reaction time may be 10-180 minutes.
In Production Method 1 according to Production Method 1 of the present invention, Step 4 is a step of introducing Compound 5 obtained in Step 3 into a solution obtained by introducing triphenylphosphine and diethyl azodicarboxylate into an organic solvent, and adding thereto a Mitsunobu reaction condition To obtain Compound (1).
Here, the 2'-hydroxy group located in the benzene ring of the compound 5 is optically conjugated to the stereocenter at the 2-position through intramolecular Mitsunobu cyclization via a stereoselective SN 2 reaction Thereby obtaining compound 1 of a pure chromanone skeleton. The intramolecular Mitsunobu ring is a key reaction capable of stereospecific introduction of the stereocenter at the 2-position of the chromanone skeleton while maintaining the original optical purity of the starting material (malic acid) under mild reaction conditions to be.
That is, the production method of the present invention can be used to produce optically pure L-malic acid in optically pure form of 2S form, or optically pure form of D-malic acid form 2R form, It is possible to synthesize all of chroman 2-carboxylate (Formula 2).
The weight ratio of triphenylphosphine and diethyl azodicarboxylate may be 1: 0.5-2, preferably 1: 1.
The organic solvent may be selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile (ACN), methanol, t-butanol, diethyl ether, diphenyl ether, diisopropyl ether DIPE), dimethylformamide (DMF), dimethyl acetamide (DMA), chlorobenzene, benzene, toluene, carbon tetrachloride (CCl 4), acetone, trichloroacetic acid, trifluoroacetic acid, hydrochloric acid, chloroform (CHCl 3), etc. Can be used alone or in combination, and tetrahydrofuran (THF) can be preferably used.
The reaction temperature in step 4 may be 0-30 ° C, preferably 0-10 ° C, and the reaction time may be 10-180 minutes.
Recipe 2: Croix 2- Carboxylic acid Method for producing derivatives
The production method 2 according to the present invention relates to a process for producing a chroman 2-carboxylic acid derivative by reducing the carbonyl group at the 4-position of the compound 1 obtained in the above Production Method 1, and this Production Method 2 is a process Can be understood.
As shown in the following Reaction Scheme 2,
The chromanone 2-carboxylic acid derivative represented by the general formula (1) is introduced into an organic solvent and hydrogen is then introduced in the presence of triethylsilane or palladium / charcoal to obtain a chromanone 2- Carboxylic acid derivative represented by formula (2), which comprises a step of reducing the carbonyl group at the 4-position of the carboxylic acid derivative to produce a chroman-2-carboxylic acid derivative represented by the formula (2) do.
[Reaction Scheme 2]
In the above Reaction Scheme 2,
R 1 to R 3 and
The chroman 2-carboxylic acid derivative represented by the formula (2) is included in the intermediate represented by the above formula (A).
In the process 2 of the present invention, the organic solvent may be at least one selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile (ACN), methanol, (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), chlorobenzene, benzene, toluene, carbon tetrachloride (CCl 4 ), acetone, trifluoroacetic acid, Hydrochloric acid aqueous solution, chloroform (CHCl 3 ), and the like can be used alone or in combination. Methanol can be preferably used.
The triethylsilane or palladium / charcoal may be introduced at 1-10% (w / w), preferably at 4-6% (w / w).
The triethylsilane or palladium / charcoal may be added with an aqueous hydrochloric acid solution at a concentration of 1-10%, preferably at a concentration of 4-6% (w / w) have.
The hydrogen can be introduced at a pressure of 0.5-3 atm and preferably at a pressure of 0.8-1.2 atm.
The chromanone 2-carboxylic acid derivative represented by the formula (1) or the chroman 2-carboxylic acid derivative represented by the formula (2), which is produced by the production process according to the present invention, can be selected only from the pure optical isomers depending on the optical form of the starting material (See Experimental Example 1).
Therefore, the intermediate represented by formula (A) according to the present invention can be usefully used for the production of active ingredients of medicines ("Fidarestat", "repinotan", "nebivolol" The process for producing the non-conjugated or chroman-2-carboxylic acid derivative is not only simple in its production process but also has the effect of producing the target compound in an optically pure form without using a chiral catalyst.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.
< Example 1a-1e > Chromanone Preparation of derivatives (compounds 1a-1e)
Step 1: Acetoxy - Chloro -4-oxo- Butanoate ( 3a One )
After adding excess acetyl chloride to L-malic acid, 50 C < / RTI > for 2 hours to form 2-acetylsuccinic anhydride. Since at room temperature was added a large excess of methanol was stirred for 5 hours caused the methanolysis reaction, and then to obtain the desired compound 3a 1 it was added to an excess of thionyl chloride.
Step 2: Preparation of compounds 4a-4e
Compound 3ba-3be (4.0 eq) and dichloromethane were added to the compound 3a (1.0 eq) obtained in the above step 1, cooled to 0-5 ° C, and AlCl 3 (8.4 eq) was slowly added thereto and stirred at room temperature. Next, ice water and concentrated hydrochloric acid were slowly added to separate the organic layer. The aqueous layer was washed with dichloromethane, and the separated organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous MgSO 4 , filtered and the solvent was removed under reduced pressure. The concentrate was purified by silica gel column chromatography ( n- hexane: ethyl acetate = 2: 1) to obtain objective compound 4a-4e.
Methyl (S) -4- (2,5-dimethoxyphenyl) -2-hydroxy-4-oxo-butanoate (4e)
The target compound was obtained in a yield of 83% from compound 3a.
1 H NMR (400 MHz, CDCl 3) δ 7.32 (d, J = 3.2 Hz, 1H), 7.04 (dd, J = 9.2, 3.2 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 3.77 ( s, 3H), 3.76 (s, 3H), 3.57 (dd, J = 18.4, 4.0 Hz, 1H), 3.47 (dd, J = 18.4, 6.0 Hz, 1H), 3.15 ( br s, 1H).
Step 3: Preparation of compounds 5a-5e
Dichloromethane was added to the compound 4a-4e (1.0 eq) obtained in the above step 2, cooled to 0-5 ° C, AlCl 3 (8.4 eq) was slowly added, and the mixture was stirred at room temperature. Next, ice water and concentrated hydrochloric acid were slowly added to separate the organic layer. The aqueous layer was washed with dichloromethane, and the separated organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous MgSO 4 , filtered and the solvent was removed under reduced pressure. The concentrate was purified by silica gel column chromatography ( n- hexane: ethyl acetate = 4: 1) to obtain the target compound 5a-5e.
Compounds obtained from compound 4 obtained from L-malic acid are compounds having a 2S stereoregular center. Compounds obtained from compound 4 obtained from D-malic acid are compounds having a 2R stereoregent. The HPLC retention time ( t R ) Are shown in the analytical data of the compounds, respectively. All the following examples and preparation examples show the reaction of the compounds prepared using L-malic acid as an example.
methyl (S) -4- (5- Fluoro -2- Hydroxyphenyl )-2- Hydroxy -4-oxo- Butanoe (5a)
The target compound was obtained in a yield of 84% from the compound 4a.
1 H NMR (400 MHz, CDCl 3) δ 11.66 (s, 1H), 7.39 (dd, 3 J H -F = 8.8, 4 J = 3.0 Hz, 1H), 7.25 (ddd, 3 J = 9.1, 3 J H- F = 7.7, 4 J = 3.0 Hz, 1H), 6.97 (dd, 3 J = 9.1, 4 J HF = 4.6 Hz, 1H), 4.69 (dd, J = 6.0, 4.0 Hz, 1H), 3.85 (s, 3H), 3.55 (dd, J = 17.6, 4.0 Hz, 1H), 3.44 (dd, J = 17.6, 6.0 Hz, 1 H), 1.60 (br s, 1 H);
13 C NMR (125 MHz, CDCl 3) δ 202.1 (4 J C -F = 2.7 Hz), 173.9, 158.8 (4 J C -F = 1.4 Hz), 154.9 (1 J C -F = 237.8 Hz), 124.7 (2 J C -F = 23.5 Hz ), 120.0 (3 J C -F = 7.3 Hz), 118.7 (3 J C -F = 6.2 Hz), 114.8 (2 J C -F = 23.2 Hz), 66.6, 52.9 , 41.9;
[?] 20 D = +13.8 ( c 2.0, CHCl 3 );
ee> 99%, Chiralpak IA column , n -hexane / ethanol = 60:40, flow rate = 1.0 mL / min, t R = 8.95 (S), 11.11 min (R);
HRMS calcd for C 11 H 12 FO 5 + [M + H] +, 243.0663. Found 243.0658.
methyl ( S ) -4- (5- Chloro -2- Hydroxyphenyl )-2- Hydroxy -4-oxo- Butanoate (5b)
The target compound was obtained in a yield of 88% from the compound 4b.
1 H NMR (400 MHz, CDCl 3) δ 11.8 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.67 ( dd, J = 6.0, 4.0 Hz, 1H), 3.83 (s, 3H), 3.56 (dd, J = 17.6, 4.0 Hz, 1H), 3.46 (dd, J = 17.6, 6.0 Hz, 1 H), 1.61 (br s, 1 H);
13 C NMR (125 MHz, CDCl 3) δ 202.1, 174.0, 161.0, 136.8, 129.1, 123.8, 120.3, 119.8, 66.5, 52.9, 41.9;
[α] 20 D = +16.8 ( c 1.0, CHCl 3);
ee > 99%, Chiralpak IA column, n -hexane / ethanol = 60:40, flow rate = 1.0 mL / min, t R = 7.88 (S), 9.66 min (R);
HRMS calcd for C 11 H 12 ClO 5 + [M + H] + , 259.0369. Found 259.0386.
methyl ( S ) -4- (5- Bromo -2- Hydroxyphenyl )-2- Hydroxy -4-oxo- Butano Ai (5c)
The target compound was obtained in a yield of 77% from the compound 4c.
1 H NMR (400 MHz, CDCl 3) δ 11.82 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.67 ( dd, J = 6.0, 4.0 Hz, 1H), 3.83 (s, 3H), 3.55 (dd, J = 17.6, 4.0 Hz, 1H), 3.45 (dd, J = 17.6, 6.0 Hz, 1 H), 1.57 (br s, 1 H);
13 C NMR (125 MHz, CDCl 3 )? 202.0, 173.9, 161.4, 139.5, 132.1, 120.4, 110.7, 66.5, 52.9, 41.9;
[α] 20 D = +15.4 ( c 1.0, CHCl 3);
ee & gt; 99%, Chiralpak IA column, n -hexane / ethanol = 60:40, flow rate = 1.0 mL / min, t R = 7.73 (S), 9.13 min (R);
HRMS calcd for C 11 H 12 BrO 5 + [M + H] +, 302.9863. Found 302.9874.
methyl ( S ) -4- (4- Methoxy -2- Hydroxyphenyl )-2- Hydroxy -4-oxo- Butanoate (5d)
The target compound was obtained in a yield of 55% from compound 4d.
1 H NMR (400 MHz, CDCl 3) δ 12.38 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 6.45 (dd, J = 8.8, 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 4.66 ( dd, J = 6.0, 4.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.51 (dd, J = 17.6, 4.0 Hz, 1H), 3.42 ( dd, J = 17.6, 6.0 Hz, 1H);
13 C NMR (125 MHz, CDCl 3 )? 200.9, 174.2, 166.5, 165.4, 131.6, 113.4, 108.0, 100.9, 67.0, 55.6, 52.8, 41.4;
[?] 20 D = +26.5 ( c 0.3, CHCl 3 );
ee> 99%, Chiralpak IA column , n -hexane / ethanol = 60:40, flow rate = 1.0 mL / min, t R = 9.59 (S), 15.04 min (R);
HRMS calcd for C 12 H 15 O 6 + [M + H] +, 255.0863. Found 255.0863.
methyl ( S ) -4- (5- Methoxy -2- Hydroxyphenyl )-2- Hydroxy -4-oxo- Butano Ai (5e)
The target compound was obtained in a yield of 51% from the compound 4e.
1 H NMR (400 MHz, CDCl 3) δ 11.52 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 1H), 4.64 ( dd, J = 6.0, 4.0 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.57 (dd, J = 17.6, 4.0 Hz, 1H), 3.47 ( dd, J = 17.6, 6.0 Hz, 1H);
13 C NMR (125 MHz, CDCl 3) δ 202.6, 174.3, 157.2, 152.1, 125.1, 119.8, 118.9, 112.5, 66.9, 56.2, 53.1, 42.1;
[α] 20 D = +8.8 ( c 0.14, CHCl 3);
ee> 98%, Chiralpak IA column , n -hexane / ethanol = 60:40, flow rate = 1.0 mL / min, t R = 8.11 (R), 11.40min (S);
HRMS calcd for C 12 H 15 O 6 + [M + H] +, 255.0863. Found 255.0854.
Step 4: Preparation of compound 1a-1e
THF, triphenylphosphine (1.5 eq) and diethyl azodicarboxylate (1.5 eq) were charged, cooled to 0-5 캜 and stirred for 15 minutes, and then the compounds 5a-5e obtained in step 3 The solution dissolved in THF was slowly added to the reaction solution and stirred at 0-5 ° C for 1 hour. The solvent was removed under reduced pressure, and the concentrate was purified by silica gel column chromatography ( n- hexane: ethyl acetate = 3: 1) to obtain the desired compound 1a-1e.
methyl ( R ) -6- Fluoro -4- Oxochroman -2- Carboxylate (1a)
The target compound was obtained in a yield of 60% from the compound 5a.
1 H NMR (400 MHz, CDCl 3) δ 7.53 (dd, 3 J H -F = 8.1, 4 J = 3.1 Hz, 1H), 7.25 (ddd, 3 J = 9.1, 3 J H -F = 7.7, 4 J = 3.1, 1H), 7.10 (dd, 3 J = 9.1, 4 J = 4.2 Hz, 1H), 5.09 (dd, J = 8.4, 5.6 Hz, 1H), 3.82 (s, 3H), 3.083.05 (m, 2H);
13 C NMR (125 MHz, CDCl 3) δ 188.8 (4 J C -F = 1.9 Hz), 168.9, 157.6 (1 J C -F = 241.7 Hz), 156.3 (4 J C -F = 1.8 Hz), 124.0 (4 J C -F = 24.5 Hz ), 121.4 (3 J C -F = 6.5 Hz), 119.9 (3 J C -F = 7.4 Hz), 112.1 (2 J C -F = 23.4 Hz), 75.3, 52.9 , 39.2;
[?] 20 D = -38.26 (c 0.85, CHCl 3) ;
ee > 99%, Chiralcel ODH column, n -hexane / ethanol = 98: 2, flow rate = 0.8 mL / min, t R = 24.98 (R), 25.13 min (S);
HRMS calcd for C 11 H 10 FO 4 + [M + H] +, 225.0558. Found 225.0571.
methyl ( R ) -6- Chloro -4- Oxochroman -2- Carboxylate (1b)
The target compound was obtained from compound 5b in a yield of 80%.
1 H NMR (400 MHz, CDCl 3) δ 7.98 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.10 (dd, J = 8.4,5.6 Hz, 1H), 3.82 (s, 3H), 3.083.05 (m, 2H);
13 C NMR (125 MHz, CDCl 3 ) 隆 188.6, 169.0, 158.7, 136.5, 128.0, 126.5, 121.8, 120.1, 75.1, 53.2, 39.4;
[?] 20 D = -50.2 ( c 1.5, CHCl 3 );
ee & gt; 99%, Chiralcel ODH column, n -hexane / ethanol = 98: 2, flow rate = 0.8 mL / min, t R = 25.13 (R), 26.56 min (S);
HRMS calcd for C 11 H 10 ClO 4 + [M + H] +, 241.0262. Found 241.0254.
methyl ( R ) -6- Bromo -4- Oxochroman -2- Carboxylate (1c)
The target compound was obtained in a yield of 55% from the compound 5c.
1 H NMR (400 MHz, CDCl 3) δ 7.98 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.10 (dd, J = 8.4,5.6 Hz, 1H), 3.82 (s, 3H), 3.063.05 (m, 2H);
13 C NMR (125 MHz, CDCl 3) δ 188.4, 169.0, 159.2, 139.3, 129.6, 122.3, 120.4, 115.2, 75.4, 53.2, 39.4;
[?] 20 D = -47.8 ( c 1.5, CHCl 3 );
ee> 99%, Chiralcel ODH column , n -hexane / ethanol = 98: 2, flow rate = 0.8 mL / min, t R = 26.37 (S), 27.73 min ( R );
HRMS calcd for C 11 H 10 BrO 4 + [M + H] +, 284.9757. Found 284.9711.
methyl ( R ) -7- Methoxy -4- Oxochroman -2- Carboxylate (1d)
The desired compound was obtained in a yield of 74% from the compound 5d.
1 H NMR (400 MHz, CDCl 3) δ 7.84 (d, J = 8.8 Hz, 1H), 6.61 (dd, J = 8.8, 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5.08 (dd, J = 8.4, 5.6 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.012.99 (dd, J = 5.6, 2.4 Hz, 2H);
13 C NMR (125 MHz, CDCl 3) δ 188.1, 169.2, 166.4, 162.1, 128.7, 114.7, 110.8, 101.0, 75.4, 55.7, 52.9, 39.1;
[α] 20 D = +12.5 ( c 2.16, CHCl 3);
ee> 99%, Chiralcel ODH column , n -hexane / 2-propanol = 90:10, flow rate = 0.8 mL / min, t R = 23.63 (S), 28.20 min (R);
HRMS calcd for C 12 H 13 O 5 + [M + H] + , 237.0758. Found 237.0756.
methyl ( R ) -6- Methoxy -4- Oxochroman -2- Carboxylate (1e)
The target compound was obtained in a yield of 56% from compound 5e.
1 H NMR (400 MHz, CDCl 3) δ 7.30 (d, J = 2.4 Hz, 1H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.05 (t, J = 7.0 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.053.03 (d, J = 7.6 Hz, 2H);
13 C NMR (125 MHz, CDCl 3) δ 189.6, 169.2, 154.7, 154.6, 125.5, 120.7, 119.4, 107.4, 75.3, 55.8, 52.9, 39.5;
[?] 20 D = -67.3 ( c 0.09, CHCl 3 );
ee > 99%; Chiralcel ODH column, n -hexane / 2 -propanol = 90:10, flow rate = 0.8 mL / min, t R = 15.83 (S), 18.64 min (R);
HRMS calcd for C 12 H 13 O 5 + [M + H] +, 236.0758. Found 237.0745.
< Example 2a, 2d, 2f > Croix Preparation of derivatives (compounds 2a, 2d, 2f)
The compound 1a, 1b or 1d obtained in Example 1 was dissolved in methanol, and a 5% w / w hydrochloric acid aqueous solution and 5% palladium / charcoal (5% w / w) ). After filtration of the reaction solution, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography ( n- hexane: ethyl acetate = 4: 1) to obtain the desired compounds 2a, 2d and 2f.
methyl ( R) -6- Fluorochroman -2- Carboxylate (2a)
The target compound was obtained in a yield of 85% from compound 1a.
1 H NMR (400 MHz, CDCl 3) δ 6.886.79 (m, 2H), 6.74 (dd, 3 J = 8.8, 4 J H -F = 2.9 Hz, 1H), 4.70 (dd, J = 7.6, 3.5 Hz, 1 H), 3.79 (s, 3H), 2.862.69 (m, 2H), 2.27 (m, IH), 2.17 (m, IH);
13 C NMR (125 MHz, CDCl 3) δ 171.4, 157.3 (1 J C -F = 237.4 Hz), 149.6 (4 J C -F = 2.1 Hz), 122.5 (3 J C -F = 7.6 Hz), 118.1 (3 J C -F = 8.1 Hz ), 115.5 (2 J C -F = 22.6 Hz), 114.6 (2 J C -F = 23.1 Hz), 73.9, 52.7, 24.5, 23.7 (4 J C -F = 1 Hz);
[?] 20 D = -10.30 ( c 0.5, CHCl 3 );
ee> 99%, Chiralpak ODH column , n -hexane / 2-propanol = 90:10, flow rate = 0.8 mL / min, t R = 7.65 (S), 13.38 min (R);
HRMS calcd for C 11 H 11 FO 3 + [M] +, 210.0687. Found 210.0681.
methyl ( R ) -7- Methoxy chroman -2- Carboxylate (2d)
The target compound was obtained in 88% yield from compound 1d.
1 H NMR (400 MHz, CDCl 3) δ 6.93 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 2.4, 1H), 6.47 (dd, J = 8.8, 2.4 Hz, 1H), 4.71 ( dd, J = 7.6, 3.5 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.772.65 (m, 2H), 2.252.
13 C NMR (125 MHz, CDCl 3 ):? 171.3, 159.1, 154.0, 129.8, 113.2, 108.0, 101.5, 73.8, 55.2, 54.4, 24.8, 22.6;
[?] 20 D = +11.6 (c 1.8, CHCl 3 );
ee > 99%, Chiralcel ODH column, n-hexane / 2-propanol = 90:10, flow rate = 0.8 mL / min, t R = 13.98 (S), 56.99 min (R);
HRMS calcd for C 12 H 15 O 4 + [M + H] +, 223.0965. Found 223.0963.
methyl ( R ) - Croix -2- Carboxylate (2f)
The target compound was obtained in a yield of 80% from compound 1b.
1 H NMR (400 MHz, CDCl 3) δ 7.11 (t, J = 7.6, 1H) 7.01 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 4.73 (dd, J = 7.6, 3.5 Hz, 1H), 3.78 (s, 3H), 2.832.74 (m, 2H), 2.302.12 (m, 2H);
13 C NMR (125 MHz, CDCl 3 )? 171.3, 153.3, 129.3, 127.5, 121.2, 120.8, 116.9, 73.7, 52.3, 24.6, 23.3;
[?] 20 D = -6.9 ( c 3.0, CHCl 3 );
ee & gt; 99%, Chiralcel ODH column, n -hexane / 2 -propanol = 90:10, flow rate = 0.8 mL / min, t R = 7.63 (S), 10.67 min (R);
HRMS calcd for C 11 H 13 O 3 + [M + H] +, 193.0859. Found 193.0858.
< Example 2b, 2c, 2e > Croix Preparation of derivatives (compounds 2b, 2c, 2e)
Triple acetic acid (20.0 eq) and triethylsilane (4.0 eq) were added to compound 1b, 1c or 1e (1.0 eq). The reaction solution was heated at 55 占 폚, heated at the same temperature for 6 hours, and cooled to room temperature. Solid sodium bicarbonate was slowly added to the reaction solution to neutralize, then purified water and diethyl ether were added. The organic layer was separated, dried over anhydrous MgSO 4 , filtered and the solvent was removed under reduced pressure. The concentrate was purified by silica gel column chromatography ( n- hexane: ethyl acetate = 4: 1) to obtain objective compounds 2b, 2c and 2e.
methyl ( R ) -6- Chlorochroman -2- Carboxylate (2b)
The target compound was obtained in a yield of 51% from compound 1b.
1 H NMR (400 MHz, CDCl 3) δ 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 2.4 Hz), 4.72 (dd 1H, J = 7.6, 3.5 Hz, 1H), 3.78 (s, 3H), 2.872.70 (m, 2H), 2.26 (m, 1H), 2.16 (m, 1H);
13 C NMR (125 MHz, CDCl 3) δ 171.0, 152.0, 128.9, 127.5, 125.5, 122.7, 118.2, 73.7, 52.3, 24.1, 23.1;
[?] 20 D = -6.9 ( c 3.0, CHCl 3 );
ee> 99%, Chiralcel ODH column , n -hexane / 2-propanol = 90:10, flow rate = 0.8 mL / min, t R = 7.68 (S), 10.88 min (R);
HRMS calcd for C 11 H 11 ClO 3 + [M] +, 226.0391. Found 226.0403.
methyl ( R ) -6- Bromock Roman -2- Carboxylate (2c)
The target compound was obtained from Compound 1c in a yield of 54%.
1 H NMR (400 MHz, CDCl 3) δ 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.73 (dd, J = 7.6, 3.5 Hz, 1H), 3.71 (s, 3H), 2.852.68 (m, 2H), 2.232.15 (m, 2H);
13 C NMR (125 MHz, CDCl 3) δ 171.2, 152.7, 132.1, 130.7, 123.5, 118.9, 113.1, 73.9, 52.7, 24.3, 23.2;
[?] 20 D = -7.1 ( c 0.5, CHCl 3 );
ee> 98%, Chiralcel ODH column , n -hexane / 2-propanol = 90:10, flow rate = 0.8 mL / min, t R = 7.87 (S), 10.54 min (R);
HRMS calcd for C 11 H 11 BrO 3 + [M] +, 269.9886. Found 269.9879.
methyl ( R ) -6- Methoxy chroman -2- Carboxylate (2e)
The target compound was obtained from Compound 1e in a yield of 35%.
1 H NMR (400 MHz, CDCl 3) δ 6.87 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.68 (d, J = 7.6, 3.5 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 2.872.70 (m, 2H), 2.302.12 (m, 2H);
13 C NMR (125 MHz, CDCl 3 )? 171.5, 153.6, 147.3, 121.7, 117.5, 113.9, 113.5, 73.8, 55.6, 52.3, 24.7, 23.6;
[?] 20 D = -5.6 ( c 0.2, CHCl 3 );
ee> 99%, Chiralcel ODH column , n -hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, t R = 9.14 (S) and 73.01 min (R);
HRMS calcd for C 12 H 14 O 4 + [M] + , 222.0887.Found 222.0892.
< Example 2g-2l > Croix 2- Carboxylic acid Preparation of derivatives (compounds 2g-2l)
To the compound 2a-2f, THF (2 mL) and methanol (1 mL) were added. 0.25 M LiOH aqueous solution (1.05 eq) was slowly added thereto, stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The diluted hydrochloric acid aqueous solution and ethyl acetate were added thereto. The organic layer was separated and concentrated under reduced pressure. The concentrate was crystallized from hexane to obtain 2 g of the target compound.
( R ) -6-fluorochroman-2-carboxylic acid (2 g)
The target compound was obtained in 96% yield from compound 2a.
1 H-NMR (400 MHz, CDCl 3) δ 6.886.80 (m, 2H), 6.75 (dd, 3 J = 8.7, 4 J H -F = 2.6 Hz, 1H), 4.74 (dd, 1H, J = 7.6, 3.5 Hz), 2.902.75 (m, 2H), 2.33 (m, 1H), 2.18 (m, 1H);
13 C NMR (125 MHz, CDCl 3) δ 175.8, 157.2 (1 J C -F = 237.9 Hz), 148.9 (4 J C -F = 2.1Hz), 122.3 (3 J C -F = 7.5Hz), 117.8 (3 J C -F = 8.1 Hz ), 114.8 (2 J C -F = 22.7 Hz), 73.2, 24.1, 23.4 (4 J C -F = 1.1 Hz);
[α] 20 D = -12.6 ( c 1.0, DMF);
ee > 99%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 6.92 (S), 9.62 min (R);
HRMS calcd for C 10 H 9 FO 3 + [M] +, 196.0530. Found 196.0531.
( R ) -6- Chlorochroman -2-carboxylic acid (2h)
The target compound was obtained in 97% yield from compound 2b.
1 H NMR (400 MHz, CDCl 3) δ 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.76 (dd, J = 7.6, 3.5 Hz, 1H), 2.902.74 (m, 2H), 2.35 (m, 1H), 2.18 (m, 1H);
13 C NMR (125 MHz, CDCl 3) δ 175.8, 151.5, 129.0, 127.9, 125.9, 122.6, 118.2, 73.2, 24.1, 23.1;
[?] 20 D = -15.5 ( c 1.0, MeOH);
ee > 98%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 6.66 (S), 8.14 min (R);
HRMS calcd for C 10 H 9 ClO 3 + [M] +, 212.0235. Found 212.0242.
( R ) -6-bromochroman-2-carboxylic acid (2i)
From the compound 2c, the desired compound was obtained in a yield of 92%. \
1 H NMR (400 MHz, CDCl 3) δ 7.23 (dd, J = 8.8, 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.77 (dd, J = 7.6, 3.5 Hz, 1H), 2.882.74 (m, 2H), 2.33 (m, 1H), 2.18 (m, 1H);
13 C NMR (125 MHz, CDCl 3) δ 174.9, 152.5, 132.1, 130.6, 125.9, 123.6, 118.6, 73.2, 24.0, 23.0;
[?] 20 D = -7.8 ( c 0.5, CHCl 3 );
ee > 99%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 6.79 (S), 8.07 min (R);
HRMS calcd for C 10 H 9 BrO 3 + [M] +, 255.9730. Found 255.9738.
( R ) -7-methoxychroman-2-carboxylic acid (2j)
The target compound was obtained in a yield of 89% from compound 2d.
1 H-NMR (400 MHz, CDCl 3) δ 6.95 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.73 ( dd, J = 7.6, 3.5 Hz, 1H), 3.76 (s, 3H), 2.812.74 (m, 2H), 2.33 (m, 1H), 2.16 (m, 1H);
C NMR 13 (125 MHz, CDCl 3) 175.8 δ, 159.2, 153.5, 129.9, 113.1, 108.3, 101.5, 73.3, 55.3, 24.6, 22.7;
[α] 20 D = +54.5 ( c 1.25, CHCl 3);
ee > 98%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 13.28 (S), 31.90 min (R);
HRMS m / z calcd for C 11 H 13 O 4 + [M + H] +, 209.0808. Found 209.0808.
( R ) -6-methoxychroman-2-carboxylic acid (2k)
The target compound was obtained from compound 2e in a yield of 80%.
1 H-NMR (400 MHz, CDCl 3) δ 6.87 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.68 (dd, J = 7.6, 3.5 Hz, 1H), 3.75 (s, 3H), 2.752.91 (m, 2H), 2.35 (m, 1H), 2.16 (m, 1H);
13 C NMR (125 MHz, CDCl 3 ) 隆 175.4, 153.9, 146.9, 121.7, 117.5, 113.9, 113.7, 73.2, 55.6, 24.6, 23.8;
[α] 20 D = -11.2 ( c 1.35, CHCl 3);
ee > 99%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 10.41 (S), 38.36 min (R);
HRMS calcd for C 11 H 12 O 4 + [M] +, 208.0730. Found 208.0741.
( R ) -Chroman-2-carboxylic acid (2l)
The target compound was obtained in a yield of 86% from compound 2f.
1 H NMR (400 MHz, CDCl 3) δ 10.55 (brs, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 7.3 Hz , 1H), 6.86 (t, J = 7.6 Hz, 1H), 4.76 (dd, J = 7.6, 3.5 Hz, 1H), 2.902.75 (m, 2H), 2.33 (m, 1H), 2.19 (m, 1H);
13 C NMR (125 MHz, CDCl 3) δ 176.3, 152.9, 129.5, 127.7, 121.1, 116.8, 73.2, 24.4, 23.3;
[α] 20 D = -6.3 ( c 1.05, MeOH);
ee > 99%, Chiralcel ODH column, n -hexane / 2-propanol / trifluoroacetic acid = 90: 10: 0.5, flow rate = 1.0 mL / min, t R = 6.68 (S), 8.19 min (R);
HRMS calcd for C 10 H 11 O 3 + [M + H] +, 179.0703. Found 179.0731.
< Experimental Example 1> The chiral of the synthesized compound HPLC Analysis
The target compounds obtained from compound 4 obtained from L-malic acid are compounds having a 2S stereoregular center, and the target compounds obtained from compound 4 obtained from D-malic acid are compounds having 2R stereoregent centers. The HPLC retention time t R ) are shown in the analytical data of the compounds in the above examples, respectively. The chiral HPLC analysis results of the synthesized compounds are summarized in Table 1 below.
[Table 1]
As shown in Table 1, the production method according to the present invention has the effect of optically and purely obtaining a high-purity compound without using a chiral catalyst having a complicated and expensive production process.
Claims (14)
(A)
(In the above formula A
R 1 and R 2 independently represent hydrogen, halogen, C 1-10 straight or branched chain alkyl, or C 1-10 straight or branched alkoxy;
R 3 represents hydrogen, straight or branched alkyl of C 1-10 , or benzyl;
X represents hydrogen, or oxygen;
An intermediate which is used in the production of a medicament active ingredient represented by the following formulas (B) to (D):
[Chemical Formula B]
≪ RTI ID = 0.0 &
[Chemical Formula D]
Acetyl chloride is added to L-malic acid to form 2-acetylsuccinic anhydride, followed by alcoholysis by adding R 3 -OH to thionyl chloride to obtain compound 3a (step 1);
Step (step 2) of obtaining compound 4 through Fridel-Crafts acylation using compound 3b and aluminum chloride;
Dissolving the compound 4 in an organic solvent, adding AlCl 3 and stirring to obtain the dimethylated compound 5 (step 3);
Triphenylphosphine and diethylazodicarboxylate in an organic solvent to obtain a compound 1 by adding the compound 5 obtained in the above step 3 and cyclizing the resulting mixture under mitsunobu reaction conditions 4): < EMI ID = 22.1 >
[Reaction Scheme 1]
(In the above Reaction Scheme 1,
R 1 to R 3 and
The chromanone 2-carboxylic acid derivative represented by the formula (1) is included in the intermediate represented by the formula (A)
The chromanone 2-carboxylic acid derivative represented by the general formula (1) is introduced into an organic solvent and then hydrogen is introduced in the presence of triethylsilane or palladium / charcoal to obtain a chromanone 2- Carboxylic acid derivative represented by formula (2), which comprises the step of reducing the carbonyl group at the 4-position of the carboxylic acid derivative to produce the chroman-2-carboxylic acid derivative represented by the formula (2)
[Reaction Scheme 2]
(In the above Reaction Scheme 2,
R 1 to R 3 and
The chroman 2-carboxylic acid derivative represented by the general formula (2) is included in the intermediate represented by the general formula (A)
The organic solvent of step 3 and step 4 is independently selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile (ACN), methanol, (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), chlorobenzene, benzene, toluene, carbon tetrachloride (CCl 4 ), acetone, trifluoroacetic acid, hydrochloric acid Aqueous solution, and chloroform (CHCl 3 ).
Wherein the reaction temperature in step 3 is 0 to 30 ° C, and the reaction time is 10 to 180 minutes.
Wherein the reaction temperature in step 4 is 0-10 ° C, and the reaction time is 10-180 minutes.
Wherein the weight ratio of triphenylphosphine and diethyl azodicarboxylate in step 4 is 1: 0.5-2.
Wherein the chromanone derivative represented by formula (1) is prepared in optically pure form or in racemic form.
The organic solvent may be selected from the group consisting of dichloromethane (DCM), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile (ACN), methanol, t-butanol, diethyl ether, diphenyl ether, diisopropyl ether as DIPE), dimethylformamide (DMF), dimethyl acetamide (DMA), chlorobenzene, benzene, toluene, carbon tetrachloride (CCl 4), acetone, trichloroacetic acid, trifluoroacetic acid, aqueous hydrochloric acid and chloroform (CHCl 3) And at least one member selected from the group consisting of the above-mentioned compounds.
Wherein the triethylsilane or palladium / charcoal is introduced at 1-10% (w / w).
Wherein the triethylsilane or palladium / charcoal is introduced together with a 1-10% strength aqueous hydrochloric acid solution.
Wherein the hydrogen is introduced at a pressure of 0.5-3 atm.
Wherein the chroman derivative represented by the general formula (2) is prepared in an optically pure form or in a racemic form.
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| US10934244B2 (en) | 2015-06-15 | 2021-03-02 | Nmd Pharma A/S | Compounds for use in treating neuromuscular disorders |
| US11147788B2 (en) | 2017-12-14 | 2021-10-19 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
| US11730714B2 (en) | 2017-12-14 | 2023-08-22 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
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| TW200815388A (en) | 2006-04-18 | 2008-04-01 | Wyeth Corp | Chromane and chromene derivatives and uses thereof |
| CN102408402A (en) * | 2011-12-27 | 2012-04-11 | 上海立科药物化学有限公司 | Synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid |
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| Angew. Chem. Int. Ed. 2013, 52, 2555-2558 |
| Tetrahedron 2000, 56, 6339-6344 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10934244B2 (en) | 2015-06-15 | 2021-03-02 | Nmd Pharma A/S | Compounds for use in treating neuromuscular disorders |
| US11147788B2 (en) | 2017-12-14 | 2021-10-19 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
| US11730714B2 (en) | 2017-12-14 | 2023-08-22 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
| EP3753560A1 (en) * | 2019-06-19 | 2020-12-23 | NMD Pharma A/S | Compounds for the treatment of neuromuscular disorders |
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